Seizures are sudden attacks or convulsions due to abnormal, hypersynchronous discharges from a population of neurons in the brain. Approximately 5-10% of people will experience one seizure in their lifetime. Febrile seizures are the most common cause of seizures in late infancy and early childhood. Though this type of seizure is prevalent throughout the world, very little is known about its mechanisms. A recent study suggested that fever induces hyperventilation and respiratory alkalosis, and that an increase in brain pH may be the proximate cause of febrile seizures. In my proposed project, I plan to test the hypothesis that temperature- and pH-induced changes of inhibitory circuits contribute to the generation of febrile seizures. First, I will examine how spontaneous and evoked extracellular field potentials in the CA1 field of the hippocampus change under conditions of high temperature and high pH. These results will allow me to determine whether high temperature, high pH or the combination of both increase hyperexcitability. Second, I will use whole-cell patch recording methods to evaluate whether temperature or pH changes alter the intrinsic membrane excitability and synaptic connections of two specific types of inhibitory interneurons or pyramidal neurons. I will use whole-cell recordings from pairs of identified interneurons or from interneuronpyramidal cell pairs. I will use small hyperpolarizing and depolarizing current steps to measure both subthreshold and active properties of each cell. I will measure changes in spontaneous synaptic activity and specific excitatory and inhibitory synaptic connections. I will correlate changes in synaptic and intrinsic properties of inhibitory interneurons with the onset of epileptiform activity in local networks. Third, I will investigate the potential role of temperature- and pH-sensitive transient receptor potential vallinoid receptor 1 (TRPV1 receptor) activation in increasing neuronal excitability during high temperature and/or pH conditions by comparing TRPV1 knockout to wild-type mice. Both in vivo and in vitro methods will be used to fully evaluate the potential effects of TRPV1 receptors. My results should contribute significantly to our understanding of the basic mechanisms of febrile seizures. With better insight into the causes of febrile seizures, we may be able to optimize prophylaxis and treatment. This work would contribute directly to the mission of NINDS to reduce the burden of neurological disease.